Spinal cord injury (SCI) often results in motor impairments and neuropathic pain. These conditions are related to changes in neural activity in regions of the spinal cord that control motor output and sensory processing. Generally, there is too little neural transmission in spinal motor pathways below the lesion, whereas there is excessive, inappropriate neural transmission in pain pathways below the lesion. It has previously been shown that delivery of small amounts of electrical current directly to motor regions of the spinal cord can increase neural transmission in motor pathways. This type of spinal stimulation is called therapeutic intraspinal microstimulation. Over time, intraspinal microstimulation can enhance motor recovery after SCI. The overall hypothesis of this proposal is that intraspinal microstimulation for motor rehabilitation can also be designed to reduce transmission in spinal pain pathways. If confirmed, this could lead to development of neuroprosthetic therapies for multimodal rehabilitation after SCI. The primary goal of this proposal is to determine the extent to which intraspinal microstimulation can reduce neural transmission in spinal pain pathways. These effects have not previously been characterized. It is known that intraspinal microstimulation activates a widespread network of non-pain-related sensory pathways that bridge the motor regions of the spinal cord and the pain-processing regions of the spinal cord. Activation of this network by peripheral nerve or spinal surface stimulation can reduce transmission in spinal pain pathways. This proposal will determine the extent to which intraspinal microstimulation can reduce transmission in pain pathways through activation of this network. This proposal will also determine whether intraspinal microstimulation promotes release and/or use of a class of natural neurotransmitters known as the monoamines. Monoamines have the unique ability to simultaneously reduce transmission in spinal pain pathways while increasing transmission in spinal motor pathways. Neurons that utilize monoamines have terminations throughout the network of neurons activated by intraspinal microstimulation. All hypotheses will be tested in vivo in anesthetized rats with chronic, motor- incomplete SCI and in rats without neurological injury. Rats of both sexes will be included. The approach includes electrophysiological, computational, pharmacological and biochemical analyses of neural activity. This proposal will advance the understanding of how intraspinal microstimulation impacts highly interconnected spinal sensorimotor networks. If support for the hypotheses is obtained, this proposal will have also identified a new strategy for neuroprosthetic therapies to deliver multimodal rehabilitation benefits. This would address two critical unmet needs of the SCI population: non-opioid treatments for SCI-related neuropathic pain and multimodal rehabilitation. It would also overcome a key limitation of clinically available spinal stimulators, which are parameterized for treatment of motor or sensory impairments alone.